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Percorrer por autor "Rotte, Nadja"

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  • Bi-allelic Mutations in M1AP Are a Frequent Cause of Meiotic Arrest and Severely Impaired Spermatogenesis Leading to Male Infertility
    Publication . Wyrwoll, Margot J.; Temel, Şehime G.; Nagirnaja, Liina; Oud, Manon S.; Lopes, Alexandra M.; van der Heijden, Godfried W.; Heald, James S.; Rotte, Nadja; Wistuba, Joachim; Wöste, Marius; Ledig, Susanne; Krenz, Henrike; Smits, Roos M.; Carvalho, Filipa; Gonçalves, João; Fietz, Daniela; Türkgenç, Burcu; Ergören, Mahmut C.; Çetinkaya, Murat; Başar, Murad; Kahraman, Semra; McEleny, Kevin; Xavier, Miguel J.; Turner, Helen; Pilatz, Adrian; Röpke, Albrecht; Dugas, Martin; Kliesch, Sabine; Neuhaus, Nina; Aston, Kenneth I.; Conrad, Donald F.; Veltman, Joris A.; Friedrich, Corinna; Tüttelmann, Frank
    Male infertility affects ∼7% of men, but its causes remain poorly understood. The most severe form is non-obstructive azoospermia (NOA), which is, in part, caused by an arrest at meiosis. So far, only a few validated disease-associated genes have been reported. To address this gap, we performed whole-exome sequencing in 58 men with unexplained meiotic arrest and identified the same homozygous frameshift variant c.676dup (p.Trp226LeufsTer4) in M1AP, encoding meiosis 1 associated protein, in three unrelated men. This variant most likely results in a truncated protein as shown in vitro by heterologous expression of mutant M1AP. Next, we screened four large cohorts of infertile men and identified three additional individuals carrying homozygous c.676dup and three carrying combinations of this and other likely causal variants in M1AP. Moreover, a homozygous missense variant, c.1166C>T (p.Pro389Leu), segregated with infertility in five men from a consanguineous Turkish family. The common phenotype between all affected men was NOA, but occasionally spermatids and rarely a few spermatozoa in the semen were observed. A similar phenotype has been described for mice with disruption of M1ap. Collectively, these findings demonstrate that mutations in M1AP are a relatively frequent cause of autosomal recessive severe spermatogenic failure and male infertility with strong clinical validity.
    2020-08-06Artigo científico Acesso restrito Ver mais
  • Variants in GCNA, X-linked germ-cell genome integrity gene, identified in men with primary spermatogenic failure
    Publication . Hardy, Jimmaline J.; Wyrwoll, Margot J.; Mcfadden, William; Malcher, Agnieszka; Rotte, Nadja; Pollock, Nijole C.; Munyoki, Sarah; Veroli, Maria V.; Houston, Brendan J.; Xavier, Miguel J.; Kasak, Laura; Punab, Margus; Laan, Maris; Kliesch, Sabine; Schlegel, Peter; Jaffe, Thomas; Hwang, Kathleen; Vukina, Josip; Brieño-Enríquez, Miguel A.; Orwig, Kyle; Yanowitz, Judith; Buszczak, Michael; Veltman, Joris A.; Oud, Manon; Nagirnaja, Liina; Olszewska, Marta; O’Bryan, Moira K.; Conrad, Donald F.; Kurpisz, Maciej; Tüttelmann, Frank; Yatsenko, Alexander N.; Conrad, Donald F.; Nagirnaja, Liina; Aston, Kenneth I.; Carrell, Douglas T.; Hotaling, James M.; Jenkins, Timothy G.; McLachlan, Rob; O’Bryan, Moira K.; Schlegel, Peter N.; Eisenberg, Michael L.; Sandlow, Jay I.; Jungheim, Emily S.; Omurtag, Kenan R.; Lopes, Alexandra M.; Seixas, Susana; Carvalho, Filipa; Fernandes, Susana; Barros, Alberto; Gonçalves, João; Caetano, Iris; Pinto, Graça; Correia, Sónia; Laan, Maris; Punab, Margus; Meyts, Ewa Rajpert-De; Jørgensen, Niels; Almstrup, Kristian; Krausz, Csilla G.; Jarvi, Keith A.; on behalf of GEMINI Consortium
    Male infertility impacts millions of couples yet, the etiology of primary infertility remains largely unknown. A critical element of successful spermatogenesis is maintenance of genome integrity. Here, we present a genomic study of spermatogenic failure (SPGF). Our initial analysis (n=176) did not reveal known gene-candidates but identifed a potentially signifcant single-nucleotide variant (SNV) in X-linked germ-cell nuclear antigen (GCNA). Together with a larger follow-up study (n=2049), 7 likely clinically relevant GCNA variants were identifed. GCNA is critical for genome integrity in male meiosis and knockout models exhibit impaired spermatogenesis and infertility. Single-cell RNA-seq and immunohistochemistry confrm human GCNA expression from spermatogonia to elongated spermatids. Five identifed SNVs were located in key functional regions, including N-terminal SUMO-interacting motif and C-terminal Spartan-like protease domain. Notably, variant p.Ala115ProfsTer7 results in an early frameshift, while Spartan-like domain missense variants p.Ser659Trp and p.Arg664Cys change conserved residues, likely afecting 3D structure. For variants within GCNA’s intrinsically disordered region, we performed computational modeling for consensus motifs. Two SNVs were predicted to impact the structure of these consensus motifs. All identifed variants have an extremely low minor allele frequency in the general population and 6 of 7 were not detected in>5000 biological fathers. Considering evidence from animal models, germ-cell-specifc expression, 3D modeling, and computational predictions for SNVs, we propose that identifed GCNA variants disrupt structure and function of the respective protein domains, ultimately arresting germ-cell division. To our knowledge, this is the frst study implicating GCNA, a key genome integrity factor, in human male infertility.
    2021-05-07Artigo científico Acesso restrito Ver mais